Genital herpes has a very high global prevalence and disease burden. Recent seroprevalence studies for the years 2005-2010 indicate that 1 out of 2 adults in the United States ages 14-49 years old is latently infected with herpes simplex type-1 (HSV-1) (Bradley et al. (2013) J. Infect. Dis. 209:325-333). Most infected individuals experience frequent, but asymptomatic episodes of virus shedding that contribute to high virus transmission rates (Hofstetter et al. (2014) Curr. Opin. Infect. Dis. 27:75-83; Tronstein et al. (2011) JAMA 305:1441-1449; Mertz (2008) J. Infect. Dis. 198:1098-1100). An increasing number of HSV-1 rather than HSV-2 infections are being observed in clinical cases (Roberts et al. (2003) Sex. Transm. Dis. 30:797-800). Importantly, genital HSV infection is considered a risk factor for acquiring human immunodeficiency virus infection (HIV) (Anuradha et al. (2008) Indian J. Dermatol. Venereol. Leprol. 74:230-233; Mugo et al. (2011) Sex. Transm. Dis. 38:1059-1066; Reynolds et al. (2003) J. Infect. Dis. 187:1513-1521; Renzi et al. (2003) J. Infect Dis. 187:19-25; Wald and Link (2002) J. Infect. Dis. 185:45-52; Sartori et al. (2011) Virol. J. 8:166), and in some geographical areas HSV-2 infection may be a contributing factor to 30-50% of new HIV infections (Brown et al. (2007) AIDS 21:1515-1523; Freeman et al. (2006) AIDS 20:73-83). A successful vaccination strategy against HSV-2 infection is predicted to have a dramatic global impact on HIV spread, prevention of genital clinical disease and neonatal infections (Freeman et al. (2009) Vaccine 27:940-946; Johnston et al. (2014) Vaccine 32:1553-1560; Gottlieb et al. (2014) Vaccine 32:1527-1535). Prior HSV immunity may confer only partial protection against HSV re-infection and the appearance of clinical disease symptoms (Hofstetter et al. (2014) Curr. Opin. Infect. Dis. 27:75-83; Blank and Haines (1973) J. Invest. Dermatol. 61:223-225). Adaptive immune responses, particularly tissue specific CD4+ and CD8+ T cells are crucial for controlling HSV infections and clearing the virus after initial infection. These T cell responses are also important in containing the virus in a latent state in ganglionic or dorsal neurons, as well as for controlling the virus after reactivation from latency (Koelle et al. (1998) J. Clin. Invest. 101:1500-1508; Milligan et al. (1998) J. Immunol. 160:6093-6100; Schiffer and Corey (2013) Nat. Med. 19:280-290; Wakim et al. (2008) Immunol. Cell Biol. 86:666-675; Zhu et al. (2007) J. Exp. Med. 204:595-603; Dudley et al. (2000) Virology 270:454-463; St. Leger and Hendricks (2011) J. Neurovirol. 17:528-534). Humoral responses have also been implicated in playing an important role in controlling HSV infectivity, spread, and the rate of reactivation from latency (Li et al. (2011) PNAS 108:4388-4393; Morrison et al. (2001) J. Virol 75:1195-1204; Seppanen et al. (2006) J. Infect. Dis. 194:571-578).
A number of vaccine approaches and candidates have been evaluated in laboratory animals and humans including purified peptides, recombinant glycoprotein subunits, inactivated, live attenuated, replication competent and replication defective whole virus, as well as DNA-based vaccines administered via different routes of immunization (reviewed in: Koelle and Corey (2003) Clin. Microbiol. Rev. 16:96-113; Roth et al. (2012) Microb. Pathog. 58:45-54; Rupp and Bernstein (2008) Expert. Opin. Emerg. Drugs 13:41-52; Dropulic and Cohen (2012) Expert Rev. Vaccines 11:1429-1440; and Zhu et al. (2014) Viruses 6:371-390). In a double-blind controlled, randomized efficacy field trial of a gD-2 HSV vaccine adjuvanted with A04 (Herpevac Trial) in 8323 women, it was found that the vaccine was 82% protective against HSV-1 genital disease, but offered no significant protection against HSV-2 genital disease (Belshe et al. (2012)N. Engl. J. Med. 366:34-43). This protection correlated with induction of neutralizing antibody against gD-2, while cellular immune responses did not appear to be involved in the observed protection (Belshe et al. (2014) J. Infect. Dis. 209:828-836; Awasthi and Friedman (2014) J. Infect. Dis. 209:813-815). A newer subunit vaccine approach currently in phase I/IIa clinical trials is based on an attempt to generate a balanced T cell and antibody response through the use of T-cell epitopes derived from the ICP4 protein and antibody generated by the gD2 glycoprotein in conjunction with the proprietary adjuvant Matrix-M (Roth et al. (2012) Microb. Pathog. 58:45-54).
In principle, live attenuated vaccines have distinct advantages over subunit and inactivated vaccines, primarily because replication of the pathogen allows for the entire repertoire of pathogen-specific antigen expression. Given the 83% nucleotide identity shared by both HSV-1 and HSV-2 genomes (Dolan et al. (1998) J. Virol 72:2010-2021), cross protective immunity may be achieved by a single safe and efficacious vaccine expressing a large enough repertoire of cross-protective antigens. Attempts at generating a live attenuated HSV vaccine have focused on the preparation of attenuated viruses that can generate robust immune responses, while minimizing potential virulence in the host. Generally, entire genes that play important roles in the virus lifecycle have been deleted or otherwise modified to attenuate the virus and allow a more robust production of humoral and cellular immune responses. Viral genome modifications include deletions in glycoprotein E (gE) (Brittle et al. (2008) J. Virol 82:8431-8441; Awasthi et al. (2012) J. Virol 86:4586-4598), multiple deletions in γ34.5, UL55-56, UL43.5, US10-12 (Prichard et al. (2005) Vaccine 23:5424-5431), UL5, UL29, UL42, ICP27 genes (van Lint et al. (2007) Virology 368:227-231; Dudek et al. (2008) Virology 372:165-175; Hoshino et al. (2008) Vaccine 26:4034-4040; Da Costa et al. (2001) Virology 288:256-263), deletion of ICP0-(Halford et al. (2011) PLoS One 6: e17748) and the UL9 gene (Akhrameyeva et al. (2011) J. Virol 85:5036-5047; Brans et al. (2009) J. Invest. Dermatol. 129:2470-2479; Brans and Yao (2010) BMC Microbiol. 10:163; Augustinova et al. (2004) J. Virol 78:5756-5765). Other live virus vaccines under study include the HSV-1 virus CJ9-gD engineered to overexpress gD1 and having a dominant negative mutation to prevent virus replication. This vaccine strain has been reported to protect guinea pigs from HSV-2 intravaginal challenge, with marked reduction in vital titer and lesion formation (Brans and Yao (2010) BMC Microbiol. 10:163).
Generation of a safe and effective replication competent HSV-1 virus is important to not only vaccinate against acquiring HSV infection and reduce HIV prevalence, but also as a safe vaccine vector that could be utilized for expression of heterologous antigens from other pathogens. HSV has many non-essential genes and can stably carry large fragments of foreign DNA. This genetic flexibility is ideal for the expression of antigens specific to other pathogens (Murphy et al. (2000) J. Virol 74:7745-7754; Watanabe et al. (2007) Virology 357:186-198). Already recombinant HSV expressing granulocyte monocyte colony stimulating factor (GM-CSF), a potent chemokine functioning in the maturation of macrophages, is being used combined with other chemotherapeutics for the treatment of squamous cell cancer of the head and neck with promising phase I/II results (Harrington et al. (2010) Clin. Cancer Res. 16:4005-4015). FDA approval for this particular HSV vaccine therapy for melanoma is expected to pave the way for the use of live-attenuated HSV-based vectors for vaccination against HSV and other pathogens. See also, U.S. Pat. App. Pub. Nos. 2013/0202639 and 2010/0297085.